Pharma Failures Actually Advance Medicine

In a recent article in Chemistry World, the respected scientist and blogger, Dr. Derek Lowe, talks about major failures in the drug industry asking “What are the projects that drug companies wish they’d never started?” Certainly, one doesn’t enter pharmaceutical R&D if he or she is seeking immediate gratification or success. Creating new medicines is extremely difficult and only one in 10 experimental medicines that enter human trials actually results in an FDA approval. Lowe acknowledges these challenges. But he also refers to these failures as “drug development sins” – a comment which seems a bit harsh. He wishes that “all such drug failures had immediate lessons as to what to avoid.”

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The main example that Lowe focuses on is torcetrapib, a drug designed to raise HDL-cholesterol (the so-called “good cholesterol”) via inhibition of cholesteryl ester transport protein (CETP). He feels that CETP is “a classic example of a drug target that would have saved everyone a great deal of time and money to avoid.” While any new project is risky, the CETP program carried a heavier than normal load in that torcetrapib had to be proven to reduce heart attacks and strokes in patients with documented heart disease in order to gain FDA approval. Such studies are difficult to carry out. In this case, Pfizer’s study known as “ILLUMINATE” was long and expensive requiring a spend upwards of $1 billion. Torcetrapib came to a rapid demise when “ILLUMINATE” was halted by the data safety monitoring board (DSMB) in midstream because the drug was not helping patients with cardiovascular disease. In fact, it might have been harming them.

The torcetrapib results were made public within hours of the DSMB ruling. But, as Lowe points out, other companies (Merck, Lilly and Roche) all proceeded with their programs despite the Pfizer results. They all believed that the torcetrapib molecule was flawed and that their own drugs did not share this flaw. At the time, CETP was the hottest target in the industry. These inhibitors had been shown to completely remodel a person’s lipid profile as they not only more than doubled HDL-cholesterol levels in patients but also significantly loweredLDL-cholesterol on top of statins. Some even dreamed that CETP inhibitors would not just stop the progression of atherosclerosis but reverse it.

Yet, as Lowe describes, none of the CETP inhibitors made it to market. Merck’s entrant, anacetrapib, got the furthest. Merck did complete its own 30,499 patient cardiovascular outcomes study (“REVEAL”) and, while its drug was modestly effective, its efficacy was not compelling. Merck decided not to pursue it further. The CETP hypothesis was dead.

In hindsight, would these companies have preferred not to spend billions of dollars on a program that did not yield a major new advance in treating cardiovascular disease? Of course, they would have rather invested in programs that succeeded. However, 25 years ago, elevation of HDL-c was viewed as the holy grail in the fight against heart disease. The studies that Pfizer and Merck carried out showed that pharmacological elevation of HDL-c had little impact on heart attacks and strokes. Furthermore, only big pharma is in a position to do these types of major studies. Billion dollar cardiovascular outcome studies are clearly too expensive for academic institutions or the NIH to conduct.

The glare of publicity that was focused on the CETP saga is not unique. The same story can be told around all the work on approaches seeking new drugs for Alzheimer’s Disease (AD). Merck, Lilly and others have carried out long term and expensive clinical trials with experimental drugs testing the amyloid hypothesis. As with CETP, there was an excellent scientific rationale for this biological target. Companies came up with excellent molecules to test the hypothesis and robust studies were carried out. Yet, these studies all failed and these failures were documented for all to see as were the lessons learned.

A great deal of transparency exists when it comes to failed clinical trials, not just in heart disease and AD but also cancers studies, rare disease research, etc. The availability of ClinicalTrials.gov has created a world where everyone is aware of the ongoing major clinical trials, the design of these trials, the number of patients recruited, etc. These trials are eagerly followed by patients, researchers, physicians, industry analysts and even payers. All of us have a stake in the outcomes of these studies.

The fact is we want big pharma to work on these difficult challenges. No other entity can do this. Yes, most fail. After such a failure, you take lessons from the experience and then move on. This is the mission of the biopharmaceutical industry. But, there are times when the trials work - wins that benefit us all.